Paget disease of bone (Mendelian Inheritance in Man, MIM 167250) is a localized monostotic (only one site is affected) or polyostotic (several sites are affected) progressive metabolic bone disorder. The disease is characterized by an increased remodeling process in which abnormal bone resorption remains coupled to new osteoblastic bone formation. The process is initiated by increases in osteoclast-mediated bone resorption, with subsequent compensatory increases in new bone formation, resulting in a disorganized mosaic of woven and lamellar bone at affected sites. This structural change produces bone that is expanded in size, less compact, more vascular, and more susceptible to deformity or fracture than is normal (Siris and Canfield 1990).
Clinical signs and symptoms will vary from one patient to the next depending on the number and location of affected skeletal sites, as well as on the rapidity of the abnormal bone turnover. It is believed that most patients are asymptomatic, but about 5% of pagetic patients present symptoms requiring treatment (Kanis 1998). The most frequent complaints are bone pain, enlargement and deformities (Kanis 1998). Other manifestations of the disease include increased susceptibility to fractures, excessive warmth over bone from hypervascularity, deafness and neurological complications caused in most instances by compression of neural tissues adjacent to pagetic bone, as well as an increased susceptibility to osteosarcomas (Hamdy 1995).
Paget disease of bone usually appears after 40 years of age (Klein and Norman 1995) and mainly affects the axial skeleton. In Western countries, Paget disease of bone is the second most common metabolic bone disorder after osteoporosis. In the United States, the disorder has an estimated frequency of 1-3% in the population over age 40 and of 8-10% for those over age 80 (Siris and Canfield 1990).
The etiology of Paget disease of bone remains unknown. However, there is compelling evidence that genetic factors play a major role in the etiology of the disorder. The disease is most common in Western Europe (Detheridge et al. 1983), North America (Rosenbaum and Hanson 1969; Guyer and Chamberlain 1980), Australia (Barker 1984) and New Zealand (Reasbeck et al. 1983) with the highest prevalence in the United Kingdom, particularly in Lancashire (prevalence >6.3%) (Barker et al. 1980). Familial risk for Paget disease of bone has been evaluated by several authors. Sofaer et al. observed a tenfold increased prevalence among the parents and siblings of patients compared to their spouses (Sofaer et al. 1983). In the United States, Siris et al. further reported an affected first-degree relative in 12% of pagetic patients and calculated a seven-fold increased risk of developing the disease for first-degree relatives (Siris et al. 1991). In Spain, Mirales-Piga et al. observed that 40% of their index cases had at least one first-degree relative affected with Paget disease of bone (Morales-Piga et al. 1995). Familial clustering of Paget disease of bone was also frequently documented (Sofaer et al. 1983; Siris et al. 1991; Morales-Piga et al. 1995; Haslam et al. 1998; Hocking et al. 2000). In the kindreds investigated to date, Paget disease of bone appeared to be transmitted with an autosomal dominant mode of inheritance with incomplete penetrance.
Suggestive evidence for linkage was first reported between Paget disease of bone and the HLA locus at 6p (Fotino et al. 1977; Tilyard et al. 1982). This potential locus was named PDB1 (MIM 167250). However, further studies did not confirm linkage at this site (Breanndan Moore and Hoffman 1988; Nance et al. 2000; Good et al. 2001), suggesting that the role of the HLA locus may be of minor importance in the etiology of Paget disease of bone.
A rare bone disorder, familial expansile osteolysis [FEO (MIM #174810)], has been mapped to chromosome 18q21-q22 (Hughes et al. 1994). Using a candidate locus approach and a large pagetic family, Cody et al. reported evidence for linkage between Paget disease of bone and the same 18q region with a LOD score of 3.40 at D18S42 (Cody et al. 1997). This locus was called PDB2 (MIM 602080). These authors proposed that the gene(s) responsible for FEO and Paget disease of bone were either closely linked or were allelic variants of the same mutant gene. Subsequently, Haslam et al. confirmed linkage to 18q in five pagetic families and observed genetic heterogeneity in three other kindreds (Haslam et al. 1998). More recent studies confirmed genetic heterogeneity of the disorder and suggested that linkage of Paget at 18q21-q22 was relatively uncommon (Hocking et al. 2000; Nance et al. 2000; Good et al. 2001).
Recently, the FEO disease gene has been identified as the TNFRSF11A gene (MIM 603499) that encodes RANK, the receptor activator of nuclear factor-κB (Hughes et al. 2000). The same heterozygotic insertion (84dup18) was detected in TNFRSF11A exon 1 in three families with FEO or FEO-related cases. One pedigree of Japanese origin with atypical Paget disease of bone also carried a 27 bp insertion (75dup27) in the TNFRSF11A gene. Their uncommon symptoms included early onset and dental problems, suggesting that these patients may suffer from a milder form of FEO or a particular early-onset form of Paget disease of bone (Leach et al. 2001). No RANK mutations have yet been reported for patients manifesting typical cases of Paget disease of bone (Hughes et al. 2000; Sparks et al. 2001). These observations show that the gene(s) causing the typical form of Paget disease of bone still remains to be characterized.